Abstract African Americans (AA) are overburdened with hypertension compared to other racial groups in the United States. The disorder often takes on a more severe form including earlier onset, resistance to treatment, and earlier end organ damage suggesting the need for personalized medicine strategies for prevention and treatment in this group. Observational studies and clinical trials have shown that commonly used antihypertensive agents exert variable blood pressure (BP) lowering effects in ethnic populations. For example, compared to Caucasians, AAs exhibit significantly poorer BP lowering response to beta-blocker, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blocker (ARB's), and a much better response to calcium channel blockers (CCBs) and diuretics when used as monotherapy. The eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure suggests calcium channel blockers and diuretics should be the first-line antihypertensive therapy for AAs. However, data show there is more variation in response to antihypertensive treatment classes within race groups than between them. Despite the clinical reliance on thiazide diuretics for AAs, no large scale pharmacogenetic discovery effort has been undertaken. Furthermore, there are concerns regarding metabolic side effects for this drug class, including abnormal glucose tolerance and hypokalemia. This is of particular importance to patients of African ancestry, who have a higher risk of developing diabetes, and often need to start treatment at a younger age. More than half of published pharmacogenetic studies do not include AAs, and, among those that do, the average sample size is small (<200). In order to overcome the limitations of previous research and enable genetic discovery of genes and variants which predict blood pressure response as well as metabolic response to thiazide diuretic, we will leverage data and specimens from 4830 AAs randomized to chlorthalidone from the Genetics of Hypertension Associated Treatment (GenHAT) study, an ancillary study of the Antihypertensive and Lipid lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Genomic discovery will be enriched for African Ancestry genetic variations, functional variation, as well as known pharmacodynamic and pharmacokinetic variants. We have established an agreement with the International Consortium for Antihypertensives Pharmacogenomics Studies (ICAPS) for validation of our findings. Genes associated with thiazide diuretic response will be evaluated for association with cardiovascular disease outcomes in AAs from GENHAT and the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS). In sum, the project will shed light on the mechanisms of thiazide diuretic response; potentially identify new treatment targets; and identify genetic markers which can optimize treatment in this high risk population.